Mosquito-borne lymphatic filariasis is a debilitating disease of major consequence throughout much of the tropics. The maintenance and transmission of lymphatic filariasis is dependent on mosquitoes species that are capable of supporting the development of the parasite to the infective third-stage larva. The response of filarioid nematodes to the environment of the mosquito vectors determines the compatibility of this parasite-host association and thereby the success or failure of transmission to the vertebrate host. How these parasites respond is determined by the genetic make-up of the mosquito vector. It has been realized for nearly 3 years that susceptibility of Aedes aegypti mosquitoes to filarial worms is under genetic control. A sex-linked recessive gene (f- m) controls susceptibility to Brugia malayi and other muscle developing filarial worms and a different sex-linked recessive gene (f-t) controls development of Malpighian tubule inhabiting parasites, e.g. Dirofilaria immitis. However, the mechanism(s) whereby gene expression influences parasite development has not been addressed. In this project, both susceptible and refractory strains of A. aegypti and the filarioid nematodes B/ malayi and D. immitis will be employed to characterize molecular differences that are associated with the ability/inability of these mosquitoes to support parasite development. Likewise, the molecular events associated with infectivity of microfilariae for their vectors will be investigated. Contemporary molecular and biochemical techniques will be used to isolate and characterize the gene(s) responsible for susceptibility and/or refractoriness and to characterize the gene products to determine how they positively or negatively influence the molecular events that must occur in the parasite if they are to develop within the mosquito environment. Determining why a particular host environment provides the necessary clues required for parasite development whereas another does not is of fundamental relevance to our understanding of the epidemiology of mosquito-borne filariasis. It also is obvious that an approach aimed at controlling lymphatic filariasis through a manipulation of the vector population would benefit from a more thorough understanding of how vector and parasite gene influence the compatibility of these associations.